The present invention relates to novel compounds, to a method for the preparation of these novel compounds, to pharmaceutical compositions containing one or more of these compounds as an active component and to methods of using these in the treatment of a wide range of stress-related disorders. The compounds have Corticotropin Releasing Factor (CRF) antagonist activity.
CRF, a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC)-derived peptide secretion from the anterior pituitary gland (Proc.Nat.Acad.Sci (USA) 80:4851 (1983); Science 213:1394 (1981)). In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system. CRF is known to produce a wide spectrum of autonomic, electrophysiological and behavioural effects consistent with a neurotransmitter or neuromodulator role in brain. Both preclinical and clinical data (relating to CRF levels, effects of exogenously administered CRF and CRF receptor density) support the hypothesis that CRF has an important role in a wide range of stress-related disorders (see: Exp. and Clin Endocrinology and Diabetes 105(2):65 (1997); and Proc.Soc.Exp.Biol.andMed 215(1):1 (1997)).
There is evidence that CRF antagonist compounds and compositions, which can attenuate the physiological responses to stress-related phenomena, have potential therapeutic utility for the treatment of a wide range of stress-related disorders, such as depression, anxiety related diseases, post traumatic stress disorder, obsessive compulsive disorder, headache, eating and feeding disorders, anorexia nervosa, gastrointestinal diseases, irritable bowel syndrome, inflammatory diseases, immune suppression, HIV infections, Alzheimer""s disease, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction and fertility problems.
It has now been found that the novel compounds having formula (I): 
wherein
A is CH or N,
ring Q is phenyl, pyridyl, pyrimidinyl or pyridazinyl, optionally substituted with one or two groups R4,
ring Y is phenyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl,
R1 and R2 are optionally branched C1-6-alkyl, C3-6-alkenyl, C3-6-alkynyl, C3-6-cycloalkyl-C1-4-alkyl, phenyl-C1-4-alkyl, 5- or 6-membered saturated or unsaturated heterocyclyl-C1-4-alkyl, which groups R1 and R2 can be substituted with OH, C1-3-alkoxy, C1-3-alkoxycarbonyl, optionally mono- or di-(C1-3-alkyl)substituted amino, halogen or cyano,
R3 is H, C1-3-alkyl optionally substituted with one or more fluorine atoms; or R3 is halogen, methoxy or ethoxy,
R4 is C1-3-alkyl optionally substituted with one or more fluorine atoms, or R4 is halogen, methoxy, ethoxy, amino, mono- or di-substituted amino, or cyano,
R5 is halogen, optionally branched C1-6-alkyl, C3-6-alkenyl, C3-6-alkynyl, C3-6-cycloalkyl -C1-4-alkyl, Oxe2x80x94(C1-6-alkyl), Sxe2x80x94(C1-6-alkyl), SO2xe2x80x94(C1-6-alkyl), hydroxy, cyano, nitro, trifluoromethyl, SO2NH2, SO2N(mono- or di-C1-4-alkyl), formyl, COxe2x80x94(C1-6-alkyl), COOH, COOxe2x80x94(C1-6-alkyl), CONH2, CON(mono- or di-C1-4-alkyl), amino, N(mono or di-C1-4-alkyl), NHCO(C1-6-alkyl), NHSO2xe2x80x94(C1-6-alkyl), which groups R5 can be identical or different, and
n has the value 0 to 4,
with the proviso that the group NR1R2 is not diethylamino, ethyl,n-propylamino or ethyl,n-butylamino, if A is CH, Q is unsubstituted phenyl, R3 is methyl, and substituent Y with the group(s) R5 is 2,4,6-trimethylphenyl,
and salts thereof have good CRF antagonist activity.
In vitro Receptor Binding Assay
The affinity of the compounds of the invention for the CRF receptor was determined by binding studies using membrane preparations of CC7-cells containing the human CRF receptor and [125I]-ovine CRF as the ligand. Separation of bound and free ligand is performed by filtration over glassfiber-filters, essentially as described by H. Herdon et al, Soc. Neurosci. Abstracts 21(2),1349,1995.
Radioactivity on the filter is measured by liquid scintillation counting. Results are expressed as IC50 values and transformed into inhibitory constants (Ki).
Assay for Functional CRF Antagonism
The antagonistic activity of the compounds of the invention was determined by functional studies using LVIP cells (Mol. and Cell Neuroscience 2:331, 1991). containing the rat CRF receptor. The origin of these cells is the mouse L-cell-line containing the cAMP responsive reporter gene construct coding for the enzyme xcex2-galactosidase, which is subsequently transfected with the plasmid containing the genes coding for rat CRF.
Formation of cAMP is stimulated with rat CRF (10xe2x88x928M) for 3 hours. The increase of cAMP results in an increase in the production of xcex2-galactosidase by stimulation of the reporter gene. The yellow product formed after administration of the substrate O-nitrophenyl-xcex2-D-Galactopyranoside is measured spectrophotometrically (405 nm). Antagonistic activity can be obtained after a 30 minutes pre-incubation with putative antagonists and subsequent incubation with the (reference) antogonist CRF for 3 hours and is expressed as pA2 values.
The novel quinoline and quinazoline derivatives of the present invention can be prepared by one of the general schemes outlined below (Scheme 1-2).
Key step in the construction of the desired 8-aryl substituted quin(az)oline derivatives is the Pd catalyzed Suzuki-Miyaura cross-coupling reaction (Chem.Rev. 95:2457, 1995). This Pd catalyzed C-C cross-coupling of relevant arylbromide precursors with aryl-boronic acid derivatives provides unique access to quin(az)oline derivatives with the substitution pattern required for CRF antagonistic activity.
Alternatively other cross-coupling methodology such as the Pd catalyzed Stille(Sn(alkyl)3) reaction may also be applied (Synthesis, 803, 1992; Advances in Metal-Organic Chemistry 5:1, 1996)
Compounds of formula I wherein A is CH can be prepared as shown in Scheme 1. 
Starting from 4-hydroxy-8-bromo-quinoline derivatives (II), (Xxe2x95x90OH) the 4-substituent can be converted into an appropriate leaving group such as Xxe2x95x90Cl, OSO2CH3 or OSO2C6H4xe2x80x94CH3 by treatment with phosphorous oxychloride, methanesulfonylchloride or p-toluenesulfonylchloride. This intermediate may be further converted into an (optionally substituted) phenolate (Xxe2x95x90OPhe) by treatment with (substituted) phenol. Compounds having formula (II) are known or can be prepared using known methods. In the next step an aryl-aryl coupling is performed between 8-bromo-quinoline derivatives (II) and the appropriate boronic acids Yxe2x80x2xe2x80x94B(OH)2, wherein Yxe2x80x2 has the same meaning as Y substituted with R5 and (R5)n. Depending on the meaning of group Q and/or Y, the Suzuki cross-coupling may also be carried out in reversed manner, i.e. using a quinoline boronic acid and the bromide Yxe2x80x2xe2x80x94Br. In still another way Stille (Sn(alkyl)3) cross-coupling methodology may be applied to effect the desired C-C bond formation. In the final step the leaving group X is substituted with NR1R2 using the free amine NHR1R2 or the corresponding acetate as such, or using the same in a high boiling solvent, such as ethylene glycol, or in an aprotic solvent such as DMSO, THF, dioxane or DMF, facilitated by the optional use of a base such as K2CO3.
The final conversion of intermediates (III) wherein X is Cl may also be performed by application of a palladium catalyzed Buchwaid-Hartwig reaction (J.Am.Chem.Soc 118, 1996, pg 7215, J.Am.Chem.Soc. 118,1996, pg 7217; J.Am.Chem.Soc 119, 1997, pg 8451) using the (secondary) amine NHR1R2 as the reagent in an aprotic solvent such as toluene, using a catalyst such as Pd2(dibenzylideneacetone)3, a base such as sodium tertiary butoxide and an additional ligand such as 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphtyl [BINAP]. Alternatively in the latter reaction the (primary) amine NH2R1 may be used, followed by an additional alkylation step with a halide R2xe2x80x94Cl, R2xe2x80x94Br or R2xe2x80x94I to give compounds of formula IV.
Intermediates having formula III wherein R3, Q, R5, Y and n have the above meanings, and X is Cl or an optionally substituted phenoxy group are novel compounds suitable for the preparation of further interesting chemical compounds.
Compounds of formula I wherein A represents N can be prepared as shown in Scheme 2. 
Starting from 4-hydroxy-8-bromo-quinazoline derivatives (V), (Xxe2x95x90OH) the 4-substituent can be converted into an appropriate leaving group such as Xxe2x95x90Cl, OSO2CH3 or OSO2C6H4xe2x80x94CH3 by treatment with phosphorous oxychloride, methanesulfonylchloride or p-toluenesulfonylchloride. Starting materials (Xxe2x95x90OH) or intermediates (Xxe2x95x90Cl) are known or can be prepared using known methods. In the next step the leaving group X is substituted with NR1R2 using the free amine NHR1R2 or the corresponding acetate as such, or using the same in a high boiling solvent, such as ethylene glycol, or in an aprotic solvent such as DMSO,THF, dioxane or DMF, facilitated by the optional use of a base such as K2CO3. In the final step aryl-aryl coupling is performed between 8-bromo-quinazoline derivatives (VI) and the appropriate boronic acids Yxe2x80x2xe2x80x94B(OH)2, wherein Yxe2x80x2 has the same meaning as Y substituted with R5 and (R5)n. Depending on the meaning of group Q and/or Y, the Suzuki cross-coupling may also be carried out in reversed fashion i.e. using a quinazoline boronic acid and the bromide Yxe2x80x2xe2x80x94Br. In still another way Stille (Sn(alkyl)3) cross-coupling methodology may be applied to effect the desired Cxe2x80x94C bond formation.